The Clinical Efficacy And Neural Mechanism Of Transcranial Direct Current Stimulation On Cerebral Small Vessel Disease Related Cognitive Impairment

BackgroundCerebral small vessel disease（CSVD）refers to a series of clinical,imaging and pathological syndromes caused by various etiologies affecting small arteries,arterioles,capillaries,venules and venules in the brain and the prevalence of CSVD increases with age.Cognitive impairment is one of the significant clinical features of CSVD.CSVD related cognitive impairment is not only one of the important components of vascular cognitive impairment（VCI）,but also closely associated with the incidence of neurodegenerative diseases such as Alzheimer’s Disease（AD）.However,different studies still have differences results in the cognitive domains involved in CSVD related cognitive impairment,and there is a lack of specific early recognition and warning indicators in China.This study aimed to evaluate the cognitive function of CSVD with white matter hyperintensities（WMHs）as the main neuroimaging manifestation using multi-dimensional neuropsychological battery and to further map the impairment spectrum of cognitive function in patients with CSVD.Although the CSVD related cognitive impairment is the consensus reached by a large number of studies,the neuroimaging mechanism of CSVD causing cognitive impairment and even vascular dementia remains to be clarified.Currently,some relatively accepted hypotheses suggest that the hippocampus plays an important role in the CSVD related cognitive impairment.Resting state functional magnetic resonance imaging（rs-f MRI）is a technique that relies on the level of blood oxygen in the brain to explore the function of brain regions.This study aims to explore the potential neuroimaging mechanism of CSVD related cognitive impairment by applying rs-f MRI technique,so as to provide new ideas for exploring possible cognitive interventions.So far,the clinical intervention for VCI is still led by the prevention and treatment of vascular risk factors,and there is currently no drug for cognitive impairment.Although therapeutic drugs derived from AD,including cholinesterase inhibitor donepezil,galantamine,rivastin and N-methyl-d-aspartate receptor antagonist Memantine,are frequently used clinically,their efficacy remains unclear.The use of non-invasive brain stimulation has made considerable progress in clinical and research.Relevant studies have shown that high-difinition transcranial direct current stimulation（HD-t DCS）is generally well tolerated.It meets basic safety standards and has shown good results in cognitive intervention in a variety of neurodegenerative diseases.Based on the neuroimaging mechanism,this study will explore the parameters of HD-t DCS in CSVD related cognitive impairment and explore the effect of HD-t DCS on CSVD related cognitive impairment and explore the neuroimaging mechanism of HD-t DCS via rs-f MRI technique.MethodsIn this study,a three-level multidimensional neuropsychology battery was used to characterize the characteristics of CSVD related cognitive impairment and explore the potential neuroimaging mechanism of its cognitive impairment.Based on the neuroimaging mechanism of CSVD related cognitive impairment,the intervention effect and neuroimaging mechanism of HD-t DCS were further explored.Study 1: In this study,Alzheimer’s Disease-8（AD-8）,Montreal Cognitive Assessment（Mo CA）,Auditory Verbal Learning Test（AVLT）,Digital Span Test（DST）,Symbol Digit Modalities Test（SDMT）,Stroop Color Word Test（SCWT）,Trail Making Test,TMT),Verbal Fluency Test（VFT）,Boston Naming Test-15（BNT-15）were used to evaluate the cognitive function for cognitive screening,general cognitive function,memory function,attention function,executive function and language function in patients with CSVD with WMHs as the main neuroimaging manifestation and healthy controls.According to Fazekas,patients with CSVD were divided into three groups:mild（1-2 points）,moderate（3-4 points）and severe（5-6 points）.The characteristics of CSVD related cognitive impairment were determined by comparing the neuropsychological test results of patients with CSVD in the three groups and healthy controls.Study 2: Based on the characteristics of CSVD related cognitive impairment,the resting-state functional connectivity（rs-FC）method was used to explore the underlying neuroimaging mechanism of CSVD related cognitive impairment.Study 3: According to the neuroimaging mechanism of CSVD related cognitive impairment discovered in Study 2,the parameters of HD-t DCS were determined,and the clinical efficacy and neuroimaging mechanism of HD-t DCS on CSVD related cognitive impairment were explored.ResultsStudy 1: A total of 264 participants including 127 healthy controls and 137 patients with CSVD were included in this study and the patients were further divided into mild WMHs group with 51 paticipants,moderate WMHs group with 44 paticipants,and severe WMHs group with 42 paticipants according to Fazekas score.There were no significant differences in age and years of education among the four groups.However,there were statistically significant differences in AD-8,Mo CA,AVLT-study,AVLT-immediate,AVLT-delay,AVLT-recognition,DST-forward,DST-backward,SDMT,TMT-A,TMT-B and VFT-fruits/vegetables（all P<0.05）.In addition,Fazekas score of patients with CSVD was negatively correlated with Mo CA,AVLT-learning,AVLT-immediate,AVLT-delay,AVLT-recognition,DST-backward,VFT-vegetable/fruit test（all P<0.05）.Study 2: A total of 140 participants were included in this study,including 36 participants in the HC group,39 participants in the mild WMHs group,37 participants in the moderate WMHs group,and 28 participants in the severe WMHs group.The rs-FC analysis between the subregions of hippocampus and whole brain showed that there were statistically significant differences between left hippocampus involved in cognitive processes（HIPc）and left dorsalateral superior frontal gyrus and right medial superior frontal gyrus in the four groups among the four groups after Gaussian Random Field correction.In addition,the rs-FC strength between HIPc and left dorsolateral superior frontal gyrus was negatively correlated with WMHs total volume and TMT-A test in patients with WMHs.The rs-FC strength between HIPc and right medial superior frontal gyrus was negatively correlated with the total volume of WMHs and TMT-A,and positively correlated with AVLT-study and AVLT-delay test（all P<0.05）.Study 3: A total of 20 patients with CSVD related cognitive impairment were included in this study.After anodal HD-t DCS targeted on the left dorsolateral prefrontal cortex（DLPFC）,the score of Mo CA,AVLT-study,AVLT-delay,AVLT-recognition,DST-backward and SDMTsignificantly increased in patients with CSVD related cognitive impairment.The rs-FC strength between HIPc and the cluter located in DLPFC found in study 2 showed significant alteration after the intervention of HD-t DCS,and the rs-FC strength decreased from 0.07（0.13）to-0.02（0.10）.ConclusionStudy 1: Cognitive impairment in CSVD manifested as impairment of general cognitive,executive,memory,and language functions,suggesting that cognitive impairment in CSVD was mainly caused by impairment of frontal lobe function.Study 2: The underlying neuroimaging mechanism of cognitive impairment of CSVD is the alteration of the hippocampal-prefrontal circuit.Study 3: Anodal HD-t DCS target on the left DLPFC is an effective way to intervent CSVD related cognitive impairment,and HD-t DCS induced hippocampal-prefrontal circuit may be the neuroimaging mechanism of improvement effect of CSVD related cognitive impairment.